There are large individual differences among humans and animals in behavioral, physiological and toxicological responses to drugs of abuse. Individual differences in human behavioral responses to drugs appear to display substantial genetic influences, although these influences may be provided by several genes. Family studies suggest several severe limitations to pedigree-based linkage approaches in drug abuse, suggesting that association studies might be more fruitful. Use of allelic association approaches also mandated careful examination of ethnic differences in populations and linkage disequilibrium at specific loci that can confound these approaches. Association studies with polymorphic markers at several different dopaminergic gene loci can test the hypothesis that interindividual differences in genes of dopaminergic neurotransmission could contribute to interindividual differences in vulnerability to substance abuse. During this fiscal year, this laboratory has continued to develop evidence that variants of the dopamine D2 receptor gene, marked by specific TaqI RFLP polymorphic markers, predispose to vulnerability to drug abuse. This work is accompanied by work documenting racial and ethnic differences in these marker frequencies, as well as striking and specific patterns of linkage disequilibrium across three markers at the D2 receptor gene locus. Interestingly, psychopathic substance abusers display gene marker frequencies no higher than those manifest by nonpsychopathic drug abusers. Studies of RFLP or VNTR polymorphic markers at the dopamine transporter and synaptic vesicular monoamine transporter loci failed to reveal allelic association in a number of the same research subjects. However, the striking linkage disequilibrium found at the D2 receptor gene locus does not exist for at least several of the dopamine transporter locus markers, rendering them less effective reporters for possible allelic variants in these dopaminergic genes.